Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting over 26 million people worldwide. It is a progressive brain disease that is characterized by dementia as well as other cognitive impairments. The neuropathology of AD is attributed to the accumulation of highly insoluble intraneuronal protein aggregates, composed of the protein tau, also known as neurofibrillar tangles (NFT). The current diagnosis of AD mostly relies on clinical symptoms and is associated with highly variable sensitivity and specificity, depending on the proficiency of the treating physician. AD can easily be confused with other neurodegenerative disorders such as Parkinson's disease (PD), which can encompass cognitive abnormalities in addition to the classic PD symptoms. The AD pathology is typically unobserved and can precede the first symptoms, caused by irreversible neuronal damage, by more than a decade.
Currently, no biochemical tests are known for the diagnosis of AD or for monitoring the progression of the disease. AD-characteristic variations in metabolites such as N-acetylaspartate (NAA), 1-(9E-hexadecenoyl)-sn-glycero-3-phosphocholine, D-glucosaminide and compounds that contain cholintrimethylamine and ethanolamines were detected in cerebrospinal fluid (CSF) and other body fluids, but no robust AD biomarkers could yet be established (Hu et al., Acta Neuropathol., 2010, 120, 385-399; Ewers et al., Exp. Gerontol. 2010, 45, 75-79; Barba et al., J. Cell Mol. Med., 2008, 12, 1477-1485; and WO 2007/045865).
WO 2000/000636 discloses a method of determining the in vivo conversion activity of a Class I, II or III gateway enzyme, said method comprising the steps of: identifying a Class I, II or III gateway enzyme to be assayed; selecting a labelled metaprobe for said enzyme, said metaprobe being selected so that when acted upon by said enzyme, at least one labelled end product that is directly detectable is produced; administering to a patient a defined amount of said labelled metaprobe; and determining the extent of conversion of said metaprobe to said labelled end product by said enzyme.
WO 2011/010103 discloses a method for classifying an individual, inter alia for having or having an increased risk of developing a pathological condition including AD, the method comprising assessing any one or more of (a) a bacterial metabolite conjugated to a sulfur-containing moiety (b) a cresol metabolite and (c) overall sulfur concentration and/or distribution of sulfur atoms in molecules in a sample taken from the individual.
WO 2010/066000 discloses a method for predicting the susceptibility of a subject to a mental or neurodegenerative disorder, including AD, the method comprising: (a) obtaining one or more biological samples from the subject; (b) determining the levels of one or more biomarkers in the sample, wherein the biomarkers are selected from pyrroles, histamine, methionine adenosyltransferase (MAT) activity, homocysteine, copper and zinc; and (c) comparing the level(s) of the biomarker(s) determined in (b) with the level(s) of said biomarker(s) from one or more control samples, wherein abnormal levels of the one or more biomarkers in the sample(s) from the subject compared to the one or more control samples is predictive of susceptibility of the subject to a mental or neurodegenerative disorder.
WO 2010/040097 discloses methods and devices for the detection of conditions or disorders including AD by detecting altered levels of stress response pathway biomarkers. Also provided are methods and reagents for identifying panels of biomarkers associated with a condition or disorder.
WO 2009/144725 to one of the inventors of the present application discloses a system for detecting volatile organic compounds derived from a breath sample, the system comprising: (a) an apparatus comprising an array of chemically sensitive sensors of single walled carbon nanotubes coated with non-polar small organic molecules, and (b) a processing unit comprising a learning and pattern recognition analyzer wherein the learning and pattern recognition analyzer receives sensor output signals and compares them to stored data.
WO 2010/064239 to one of the inventors of the present application discloses a system comprising an array of sensors for measuring volatile organic compounds as biomarkers for diagnosis, prognosis and monitoring of renal insufficiencies, the system comprises an array of sensors comprising a (semi-) conductive random network of single-walled carbon nanotubes (SWCNTs) coated with an organic coating which comprises oligomers or polymers modified with at least one polar functional group, in conjunction with learning and pattern recognition algorithms.
WO 2009/066293 to one of the inventors of the present application discloses an apparatus comprising at least one chemically sensitive sensor for detecting volatile and non-volatile compounds, wherein the chemically sensitive sensor comprises cubic nanoparticle conductive cores capped with an organic coating. Methods of use thereof in identifying various disease biomarkers, and in food quality and environmental control are disclosed.
WO 2010/079490 to one of the inventors of the present application discloses a sensor array for detecting biomarkers for cancer in breath samples. The sensor array is based on 2D films or 3D assemblies of conductive nanoparticles capped with an organic coating wherein the nanoparticles are characterized by a narrow size distribution.
WO 2008/124187 discloses a method for diagnosis or monitoring a disease or condition in an individual comprising: (a) collecting one or more biological sample from said individual, wherein the biological sample(s) contain proteins, lipids and nucleic acids of the individual; (b) analyzing the proteins and/or lipids from a biological sample to determine selective metabolites and oxidation products of arachidonic acid (AHA), docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA); wherein said analyzing results in a metabolic determination of oxidative stress and lipids; and (c) analyzing the nucleic acids from a biological sample to determine the genotype and/or expression of genes involved in oxidative stress and/or lipid metabolism; wherein the existence or severity of a disease or condition is determined.
WO 2007/086986 discloses a method for detecting a target analyte/biomarker in exhaled breath comprising: a) exposing to the exhaled breath a molecular recognition agent capable of selectively binding to the target analyte/biomarker, wherein the molecular recognition agent is linked with a signaling agent; and b) detecting a signal generated by the signaling agent.
WO 2005/079669 discloses a method for diagnosing a predetermined condition in a subject including AD, said method comprising the steps of: (i) determining the amount, or relative amount, of a predetermined diagnostic species in a first breath sample; (ii) determining the amount, or relative amount, of said predetermined diagnostic species in a second breath sample; (iii) relating the results of steps (i) and (ii) with the presence or absence of said predetermined condition; wherein said first sample and second sample are ex vivo and are derived from different phases of a breathing cycle of said subject.
WO 2003/094932 discloses the use of carbon monoxide (CO) as a biomarker and therapeutic agent of conditions and disease states including, inter alia, AD.
WO 2000/061002 discloses a method for the assessment of psychiatric or neurological conditions, including AD, the method comprising determining the presence and/or amount of ethane or butane in the expired breath of the patient.
At present, no simple and reliable technique is available for early diagnosis of AD. There further remains an unmet need for the monitoring of AD progression using breath biomarkers thus affording adequate AD management.